The term “short stature” is medically defined as height more than two standard deviation (−2SD) below the mean height of the population of individuals of the same sex and the same age. When this criterion is fulfilled with respect to an individual, such an individual is diagnosed as a short-statured syndrome or dwarfism. The short stature is roughly divided into: short stature caused by endocrine abnormalities such as hyposecretion of growth hormones or insulin-like growth factor-I (IGF-I); short stature caused by non-endocrine abnormalities, including familial short stature, fetal hypoplastic short stature, or chromosomal abnormality-caused short stature; and secondary short stature caused by chemotherapy or radiation therapy.
The short stature or dwarfism has been treated so far by administration of growth hormones or by orthopedic surgeries, such as replacement of a hip joint with an artificial joint or limb lengthening. In the case of limb lengthening, the bone is surgically cut at age 10 or older and the body height is gradually extended using a special machine (a limb lengthener) over a period of around half a year. This operation, however, imposes severe pain on the patient. In the case of growth hormone therapy, height growth can be improved via periodical injection of growth hormones from early childhood; however, growth would be terminated upon discontinuation of injection. Such treatment techniques are not intended to treat diseases, and are not considered to be ideal from the viewpoint of the quality of life (QOL) of patients (American Journal of Medical Genetics 1997, 72: 71-76; European Journal of Endocrinology 1998; 138: 275-280). The short stature caused by endocrine abnormalities is a disease capable of treating with drugs such as recombinant growth hormones or IGF-I. In contrast, the cause of a nonendocrine abnormality-caused short stature like familial short stature or fetal hypoplastic short stature has not yet been elucidated. Since the effect of growth hormones on nonendocrine abnormality-caused short stature has not been approved, there are no effective therapeutic agents against such short stature (the Merck Manual, 17th edition, 1999, Nikkei Business Publications, Inc./Nikkei BP Publishing Center, Inc., Japan). Under these circumstances, development of therapeutic agents based on new mechanisms has been demanded.
Guanyl cyclase (GC) is a membrane protein belonging to the enzyme family that catalyzes the synthesis of the second messenger cGMP from GTP, and its examples include GC-A, GC-B, . . . , and GC-F. GC-B is found mainly in vascular endothelial cells, and thought to be involved in relaxation of the smooth muscle.
Natriuretic peptides (NPs) are divided into ANP (atrial sodium peptide), BNP (brain natriuretic peptide) and CNP (type c natriuretic peptide), and they are thought to elevate an intracellular cGMP level through two guanyl cyclase conjugated receptors (NPR-A for ANP and BNP, and NPR-B for CNP) and to perform intracellular signal transduction mediated by a plurality of cGMP effecter molecules (Ann Rev Biochem 1991; 60: 229-255). NPs have been reported to play an important role in the control of humoral homeostasis and blood pressure (J Clin Invest 1987; 93:1911-1921, J Clin Invest 1994; 87: 1402-1412), and their expression and biological activity in various tissues other than the cardiovascular system are known (Endocrinol 1991; 129:1104-1106, Ann Rev Biochem 1991; 60: 553-575). Concerning cartilage bones, effectiveness of overexpression of BNP (Proc. Natl. Acad. Sci., U.S.A., 1998, 95: 2337-2342) or CNP in the joints on the treatment of achondrogenesis resulting from mutation of a fibroblast growth factor receptor 3 (FGFR3) gene has been reported (Nat. Med., 2004, 10 (1): 80-86; Japanese Patent Publication No. 2003-113116 A).
An object of the present invention is to provide a composition for increasing a body height of a patient with short stature or an individual other than patients with short stature, who is free from FGFR3 abnormality, for therapeutic, cosmetic, or other purposes.
It is another object of the present invention to provide a method for increasing a body height in a patient with short stature or an individual other than patients with short stature by the activation of GC-B, wherein said patient and individual are both free from FGFR3 abnormality.
A further object of the present invention is to provide a method for screening for an agent for increasing a body height using the activity of GC-B as an indication.
A still further object of the present invention is to provide a method for extending a cartilage bone free from FGFR3 abnormality by the activation of GC-B.